HAL Id: hal-01618298
https://hal.archives-ouvertes.fr/hal-01618298
Submitted on 7 Feb 2018
HAL is a multi-disciplinary open access
archive for the deposit and dissemination of
sci-entific research documents, whether they are
pub-lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.
L’archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d’enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.
Comparative Study of Two Processes to Improve the
Bioavailability of an Active Pharmaceutical Ingredient:
Kneading and Supercritical Technology
Jacques Fages, Élisabeth Rodier, Alain Chamayou, Michel Baron
To cite this version:
Jacques Fages, Élisabeth Rodier, Alain Chamayou, Michel Baron. Comparative Study of Two
Pro-cesses to Improve the Bioavailability of an Active Pharmaceutical Ingredient: Kneading and
Super-critical Technology. kona powder and particle journal, 2007, 25, p. 217-229. �hal-01618298�
Introduction
An important parameter in pharmaceutical formu-lations is the bioavailability of the active substance. Many new Active Pharmaceutical Ingredients (API) are very poorly water soluble. Their absorption by the human organism is therefore extremely low and difficult to control. In case of very low solubility, one of the first rule of the formulation process is to in-crease this bioavailability by enhancement of the dis-solution rate and apparent solubility. A way to reach this goal is to associate these low-solubility active molecules with cyclodextrins (CDs) by forming inclu-sion complexes.
Although many articles describe the interactions between active molecules and CD only few papers deal with the processes used for such complexes production. Four classes of processes can be dis-tinguished: liquid (co-precipitation, co-evaporation, spray-drying, freeze-drying, neutralisation), using supercritical CO2, semi-solid (kneading), and solid
(sealed-heating, high energy co-grinding). Anyhow, the success of a drug delivery technology and of the process used to produce it, are highly depen-dent on whether it can be scaled-up, is reproducible and allows for cost-effective manufacturing. This paper is focused on the comparison of two of them: kneading (a) and supercritical fluid processing (b), in the case of the complexation of Eflucimibe with γ-cyclodextrins (γ-CDs).
A first description of the kneading process has been presented by Gil１） and Hutin２）. The use of
su-percritical carbon dioxide (SC-CO2) for particle
gen-eration of pharmaceuticals and for improving their
Comparative Study of Two Processes to Improve the
Bioavailability of an Active Pharmaceutical Ingredient:
Kneading and Supercritical Technology
†
Jacques Fages*, Elisabeth Rodier, Alain Chamayou and Michel Baron
Ecole des Mines d’Albi, RAPSODEE Research Centre1
Abstract
Two processes have been developed for the enhancement of bioavailability of a poorly-soluble active substance, Eflucimibe by associating it with γ-CD (γ-cyclodextrin).
In the first process (process a), Eflucimibe was added to an aqueous slurry of CD, in a kneading device. The evolution of the transformation was followed by DSC, FTIR, Eflucimibe dissolution kinet-ics, as well as semi-solid state change of the mixture. An optimization of the process was performed and a prevision of the scaling-up was made using dimensionless numbers. This process is simple and robust. It can be compatible at the industrial scale with a good economy and appropriate control.
In the second process (process b), Eflucimibe and CD are co-crystallized using an anti-solvent process, dimethylsulfoxide being the solvent and supercritical carbon dioxide being the anti-solvent. Then, the co-crystallized powder is held in a static mode under supercritical conditions for several hours. A final stripping step, is used to extract the residual solvent. The coupling of the first two steps brings about a significant synergistic effect to improve the dissolution rate of the drug.
Both processes resulted in a strong acceleration of the in vitro dissolution rate of the drug. Finally, in an in vivo test, these two processes appeared to be very effective, process (a) and (b) giving re-spectively an 8-fold and 11-fold increase in bioavailability.
Keywords: Eflucimibe, Cyclodextrin, Kneading, Supercritical CO2, Scale-up, Bioavailability
† Accepted: September 12,2007 1 Campus Jarlard, 81013 Albi, France ＊ Corresponding author
TEL: +33-5 -63-49-31-41 FAX: +33-5-63-49-30-25
bioavailability is well documented３）.
These processes (a) and (b) will be described in the case of Eflucimibe, a highly potent acyl-coenzyme A O-acyltransferase (ACAT) inhibitor with the molec-ular formula C29H43NO2S (Fig. 1), treating
hypercho-lesterolemia. Its structure and extreme hydrophobic-ity confers to this molecule a very poor solubilhydrophobic-ity in water.
In terms of solubility and permeability, according to the Biopharmaceutics Classification System BCS４）,
it can be considered as a Class Ⅳ compound (Table 1), with low solubility in aqueous media and low per-meability through the intestinal mucosa. The result is a high variability in blood level when formulated in lactose capsules１） and a poor bioavailability.
γ-CD is a cyclic octasaccharide (Fig. 2) obtained by enzymatic degradation of starch, consisting of 8 D-Glucose units, and presenting an hydrophilic exter-nal wall and an hydrophobic interexter-nal cavity that can receive organic molecules.
This configuration allows to perform the
dissolu-tion of the drug substance in aqueous soludissolu-tions and to liberate it by dissociation of the complex, followed by the absorption of the drug in the circulatory sys-tem (Fig. 3)
Eflucimibe was provided by Pierre Fabre Labora-tories (Castres, France).γ-CD was purchased from Wacker-Chemie GmbH (München, Germany). 1. The Kneading Process
The kneading process can be considered as a mechanochemical process carried out in the pres-ence of a small amount of solvent (water or other) that acts as lubricant for the molecular diffusion. This catalyst behaviour of the solid sate process, results in a smooth transformation of the reactants into the fi-nal products avoiding the contamination of the active ingredient by secondary transformation not suitable in the production of pharmaceutical products５）.
We applied this process to the complexation of Eflucimibe with γ-CD.
Fig. 1 Structure of Eflucimibe.
Table 1 Biopharmaceutics Classification System
High Solubility Low Solubility
High Permeability Class I Class II
Low Permeability Class III Class IV
Fig. 2 Structure of γ cyclodextrin.
Experimental set-up and process Kneading equipment
The kneading equipment was a 316 L stainless steel Aoustin® kneader with dual Z blades (Fig. 4).
Those dual blades take up an important relative vol-ume and the space between the wall of the kneader and the side of the blades is very small, initiating large shearing effects. Two scales of this apparatus were used : MX1 with a nominal capacity of 1.5 L and MX2 with a nominal capacity of 3 L.
Kneading process
The blade speed of the kneader was fixed at 50 rpm. γ-CD was introduced in the kneader bowl kept at 305 K (optimized temperature2)); Purified water
(1 ml.min-1) is added to a mixture of Eflucimibe/CD
at a (1:2) molar ratio and the blend is kneaded thor-oughly while following simultaneously the
tempera-ture and torque measurement until the increasing of the viscosity of the mixture which is a characteristic of the complexation (Fig. 5)1). The final mass
quan-tity of purified water in the mixture was 27.5 %. The evolution of the transformation was followed by DSC (Differential Scanning Calorimetry), FTIR (Fourier Transform Infrared Spectroscopy), Eflucimibe dis-solution kinetics, as well as semi-solid state change of the mixture (Fig. 6). For each sample taken, the paste obtained was dried at 313 K for 12h using a vacuum oven. The dried product was sieved below 50μm. The area called “ENERGY” under the curve is a characteristic of the process. The interaction between Eflucimibe and CD occurs if this area is suf-ficient.
Several approaches are available for controlling
Fig. 5 Torque and temperature versus time during complexation of
Eflu-cimibe and cyclodextrin.
Fig. 4 Kneading equipment.
the process at one scale and for scaling-up to an-other scale. The experimental design approach can be a powerful tool to model processes. Three input variables that are water extent, blade speed and temperature have already been selected. Two output variables are also selected : dessolution rate of the product and the extent of inclusion determined by DSC. The principle is to determine for each output variables a model involving each input variables and their interactions. By comparison of the models it is possible to optimise the different input variables to obtain a compromise between them and achieve the desired results of the output variables. The effect of the following process parameters on the extent
of inclusion and solubility enhancement (Fig. 7)
has been investigated by means of an experimental design analysed at MX1 scale which allows the defini-tion of an optimised experiment with those operating conditions.
DSC and thermoanalytical procedure for the de-termination of the percentage of transformed Eflucimibe (Y)
Thermal analysis by DSC was carried out using a Perkin Elmer DSC 7 apparatus. Samples of 3 mg were introduced into sealed aluminium pans.
DSC scans were performed in triplicate under nitrogen, at a heating rate of 5 K.min-1 in the
tempera-ture range of 303 K to 378 K. Heats of fusion were automatically determined by the software following calibration with Indium (28.4 J.g-1), using integration
of the areas under the DSC endothermic peaks of melting. A thermoanalytical procedure can be applied to quantify the interaction yield6). F is the fraction by
weight of Eflucimibe in the starting mixture and N,
the fraction by weight of Eflucimibe in the initial state after the kneading step. The percentage of trans-formed Eflucimibe after interaction, Y, is calculated according to equation (1) (1) where N is calculated according to DSC results and equation (2)
(2) FTIR spectroscopy and spectroscopic procedure to follow Eflucimibe interaction
The infrared spectra were recorded on a Nicolet FTIR spectrometer. The analysed component was dispersed in KBr medium in solid state before acqui-sition.
The Eflucimibe interaction with CD led to a de-crease of Eflucimibe band intensity. In order to quantify this modification, the Beer-Lambert law was applied by the determination of Log I0/I with I0
cor-responding to the absorbance at 1572 cm-1 (spectral
region where Eflucimibe and CD do not present spec-tral band) and I corresponding to absorbance at 1537 cm-1 (spectral region where only Eflucimibe presents
spectral band).
Determination of Eflucimibe solubilisation ki-netics
The Eflucimibe solubilisation kinetics were de-termined with samples corresponding to 50 mg of Eflucimibe. These samples were added to 100 ml of the solubilisation medium corresponding to an aque-ous solution containing 5 % (w/V) of sodium lauryl sulfate. The samples were continously stirred while remaining in a water bath at 310 K (normalized tem-perature for pharmaceutical test). At various time in-tervals, samples were withdrawn and filtered through 0.45μm membrane. The amount of Eflucimibe dis-solved was determined by HPLC using UV detection at 220 nm. Acetonitrile and purified water at 82 : 18 V/V was run at 1ml.min-1 flow rate through a reverse
phase C8 column.
Use of dimensionless numbers to study the scaling-up
The principle of the methodology is to solve the re-lationship on one scale and then to use it to calculate the power required on another scale to obtain a same finished product quality.
We applied the Buckingham theorem7); the main
physical variables are found to be:
The power number : Np =
The Reynolds number : Re =
The Froude number : Fr =
The fill ratio of the kneader : H/R
The blade size : (R)/L
Where g is the gravitational constant, R, L respective-ly the blade, length and radius, N the blade rotational speed, h the height of powder, ρ the bulk density of the powder, η the viscosity and ΔP the net blade power consumption that is to say total power less power required to stir the dry powder.
Hence, the physical phenomena before complex-ation can be described by a relcomplex-ationship as follows (equation 3) :
Np = f(Re, Fr, H/R, (R)/L). (3)
Results and discussion
The process is fast and evolves as shown on Fig. 6 The complexation induced a dramatic increase of Eflucimibe dissolution rate (Fig. 7)
An optimization of the process was performed and a prevision of the scaling-up was made using dimen-sionless numbers.
As the viscosity is unknown, it was replaced by the mean torque before complexation and the dimension-less Re becomes a pseudo-Reynolds ψRe8).
The relationship between the power number and the other dimensionless group is established by Fig. 8 and equation 4:
Np = k (ψRe.Fr.(H/R).(R/L))-n
k = 338.4 (m3.s)-n and n = 0.84 (4)
Where the correlation coefficient is 0.99 for 17 ex-periments.
One experiments has been repeated three times under the same conditions to test the reproducibility of the process. The resulting points on the scale-up relationship (Fig. 8 and 9) were very close to an-other.
Three experiments carried out under the opti-mised conditions give good results in agreement with the dimensionless relationship.
Those equations are applicable for a series of geo-metrically similar kneader of different sizes. It was possible to check those predictions at a twice scale, with an MX2 kneader. Plot of Np versus the combina-tion of the four remaining dimensionless numbers
are presented in Fig. 9 with those last experiments. The relationship between the power number and the other dimensionless group stay the same as equa-tion 4 where the correlaequa-tion coefficient is 0.99 for 17 experiments at MX1 scale and 6 experiments at MX2 scale.
The results show that the process is fast, simple and robust. Using dimensionless numbers it can be conducted at the industrial scale with a good econo-my and appropriately monitored using technologies recommended by FDA’s Process Analytical Technol-ogy (PAT).
2. The Supercritical Process
SC-CO2 has recently emerged as a new medium for
complexation with CD due to its properties of improved
Fig. 9 Ln (Np) versus Ln (ψRe.Fr.H/R.R/L)experimental results at the MX2 scale.
mass transfer and increased solvating power9), 10).
We have implemented a new process by combining a co-crystallisation anti-solvent process SAS11) with a
maturing step9) and adding finally a stripping step to
extract residual solvent.
Experimental set-up and procedures
All experiments were performed in a flexible su-percritical machine (Separex, France) shown on Fig. 10.
Dimethylsulfoxide (DMSO) as the solvent and SC-CO2 as the antisolvent were used in the SAS
ex-periments. CD and Eflucimibe were both dissolved
in DMSO. This solution was injected into the CO2
stream in the mixing chamber of a nozzle (Spraying System, France), and sprayed into an expansion ves-sel. The powder formed was collected in a porous bag placed in the expansion vessel after depressurisa-tion.
For the maturing step, 7 g of Eflucimibe/CD pow-der (with a molar ratio of 1/2) were wetted by 2.33 g of water (corresponding to 25 mass% of total powder) and placed in a 2 l autoclave. This vessel was filled with SC-CO2 at the desired pressure and temperature
and left for several hours without any agitation. The powder was recovered after gentle depressurisation.
In the final stripping step, the powder was submit-ted to a continuous flow of SC- CO2 for two hours in a
stainless steel basket.
Powder characterisations
After each step, composition of the powder ob-tained was determined. Eflucimibe content was measured by HPLC, residual DMSO content by GPC and water content with a Karl Fisher titrator.γ-CD content was then calculated from all these results. Eflucimibe, DMSO and water contents are given in mass percentage of the total powder mixture.
The DSC thermograms were performed on a Per-kin-Elmer, DSC-7 calorimeter equipped with a ther-mal flux cell device. The DSC patterns of the samples (2-3 mg) were obtained between 313 K and 413 K at a heating rate of 5K/min under a N2 gas stream. They
are shown in Fig. 11, for the initial powder mixture (Fig. 11a) and after each processing step (Fig. 11 b, c and d). By integrating the melting peak of drug in DSC thermograms, which is generated by the crystalline form of the powder, and knowing indepen-dently the total drug content, it is possible to calcu-late the amount of non-crystalline Eflucimibe. This last one corresponds to the drug not visible on DSC thermogram, hence drug molecule likely implied in interactions with CD and microcrystalline aggregates dispersed among CD matrix. It acts as an indicator of the level of drug/CD complexation.
To estimate the dissolution rate improvement, in
vitro dissolution studies were performed at 310 K
as described elsewhere12). The dissolution rate is
defined as the Eflucimibe content dissolved in the medium after a fixed time, expressed in μg of Eflu-cimibe per ml of solution. The dissolution curves are
presented on Fig. 12 for the physical mixture (a), and after each processing step (b, c and d).
Co-crystallisation step
This step has been conducted according to previ-ously published procedure by Rodier et al.13). On
ESEM microphotographs (not shown) an intimate mixture of both components can be seen: large CD particles with drug fibres deposited on them.
The Eflucimibe melting temperature (Fig. 11a)
of the physical mixture with γ-CD was found to be 402 K. For the co-crystallised powder, we observed a melting temperature of 399.1 ± 0.6 K (mean of 29 experiments). In addition, a part of Eflucimibe con-tained in the mixture after co-crystallisation is not visible by DSC.
After this step, the dissolution rate was higher than that of the physical mixture with the same profile (Fig. 12b). It was no longer correlated to the specif-ic surface of the powder, whspecif-ich can be tuned by the operating conditions with Eflucimibe alone14) but not
in the presence of CD. For instance, the mass ratio
CO2 /DMSO, had no effect on the composition and
dissolution rate of the resulting powder. On the con-trary, decreasing the mole ratio of Eflucimibe to CD in the initial mixture from 1/1 to 1/3 increased the drug crystallisation yield from 40 % to 70 % (w/w). This yield is defined as the ratio between the mass of powder formed and the mass of powder initially
dis-solved in DMSO. Maturing step
This process, first described by Van Hees et al 9) is
very effective for complexation. Several drugs have been processed successfully with this method15, 16).
After this step, drug fibres are not so clearly distin-guishable from CD particles on microphotographs (not shown). Furthermore, only a very small Eflu-cimibe melting peak can be seen on DSC thermo-gram (Fig. 11c). A strong increase in the drug dis-solution profile is noticed with a peak at 500mg/ml
Fig. 11 DSC curve of physical mixture (a); co-crystallised powder (b); powder after co-crystallisation and
maturing (c); powder after co-crystallisation, maturing and stripping (d).
Fig. 12 Dissolution curve of crystallised powder (b); powder after
co-crystallisation and maturing step (c); powder after co-crystallisa-tion, maturing step and stripping (d); physical mixture (a).
(Fig. 12c).
The influence of CO2 density and viscosity was
evaluated on the dissolution rate. Both the non-crystalline drug content and the dissolution rate increase when CO2 density and viscosity decrease as
shown on Table 2. Besides, the non-crystalline drug content is not linked to the solubility of the active substance in CO2. This suggests that mass transfer
would limit the maturing step and that CO2 solvent
power is not a crucial point.
In addition, the influence of the operating time of this static step has been studied. A classical satura-tion-shape evolution was noticed: up to 6 hours, the powder composition is modified and dissolution ki-netics increases, while both remain constant beyond 6 hours.
We have also studied the effect of the initial mix-ture composition. Three mixmix-tures having the same mass composition were wetted, placed in the auto-clave and submitted to the same conditions (30 MPa, 373 K, 16 hours). The first mixture was composed of the initial drug and CD, the second of drug and
CD crystallised separately by SAS process and the third of drug and CD co-crystallised by SAS. Table 3 shows the dissolution rate after 2 hours for each mix-ture at different stages: just after mixing, just after adding water and after the static maturing step.
This table provides also the specific surface area of the mixtures. Comparison of the first and the sec-ond mixtures before the static step confirms that the amount of dissolved drug increases with the specific surface area. Comparing the second and the third mixtures, it appears that the amount of dissolved drug is no longer correlated to the specific surface area. Therefore, the static step may enhance the dispersion of the drug into the CD matrix and thus it may increase the dissolved drug concentration in all cases. However, the improvement of the compound dissolution is significantly higher for the before hand co-crystallised powder. In conclusion, a strong syner-gistic effect is obtained by coupling the co-crystallisa-tion and the static steps.
Table 2 Effect of the maturing step on Eflucimibe-crystalline content and dissolution rate as a function of CO2 density and viscosity
T, K P, MPa ρ, kg/m3 Pa.sμ, SEflucimibe/CO2, ×107 , mole fraction Non-crystalline Eflucimibe, mass% Dissolution rate at 2h, μg/ml 373 10 278 2.40 10-5 54 98.8 678.4 313 10 564 3.78 10-5 1 88.5 522.9 373 30 644 4.70 10-5 571 88.6 503 353 30 734 5.41 10-5 169 84.1 596.5 313 20 830 6.16 10-5 5 82.3 487.9 333 30 831 6.26 10-5 46 83.2 499 313 30 928 7.20 10-5 11 73.8 336.9
Table 3 Maturing step, dissolution rates and specific surface areas as a function of the initial mixture
Eflucimibe Initial powder SAS treated Co-crystallised
Cyclodextrin Initial Cavamax SAS treated Co-crystallised
BET specific surface of the mixture, m2/g 2.3 17.1 8.6
BET specific surface of the Eflucimibe alone,
m2/g 7.5 54 ─
Dissolution rate at 2 hours of the mixture,
just after mixing the powders, μg/ml 19 69 100
Dissolution rate at 2 hours of the mixture,
after adding maturing water, μg/ml 33 58 88
Dissolution rate at 2 hours of the mixture,
Stripping step
After the stripping step, a homogeneous aspect of the powder was observed (not shown). This can be linked with the complete disappearance of the Eflu-cimibe melting peak (Fig. 11d) and in a sharper and higher dissolution peak (Fig. 12d). The aim of the stripping step was to decrease the solvent content be-low 5000 ppm, which is the pharmaceutical standard for a class III solvent. Decreasing the solvent below this threshold is possible, but some drug extraction will be unavoidable, which is the main drawback of this step. In addition, the stripping step has dehydrat-ed the CD: roughly, water content drops from 13%mass
to 2-3%mass. Some of the adsorbed water onto CD was
dissolved into the SC-CO2 flowing through the bed of
powder, thus dehydrating it. This explains the fast initial dissolution rate due to its enhanced hygroscop-icity.
Dissolution kinetics
The dissolution kinetics evolves in the following way. First, the dissolving medium diffuses into the CD matrix containing Eflucimibe. Then, Eflucimibe is dispersed into the dissolving medium and is tem-porarily stabilized into SDS micelles corresponding to the maximum dissolved drug concentration on Fig. 12. Then follows a recrystallization of Eflu-cimibe leading back, after a sufficient period of time (at least 20 h), to the solubility of pure Eflucimibe in this dissolving medium, (that is around 100 μg/ml). According to this scenario, the increase in dissolved drug concentration does not correspond to a true dis-solution of the active substance, but to the generation of a metastable colloidal dispersion of SDS micelles including drug. Finally, the acceleration of the dis-solution kinetics after the stripping step may be due to the acceleration and amplification of the first dis-solution step, which is the diffusion of the aqueous medium through the dehydrated CD matrix
Finally, this new process using supercritical CO2
and γ-CD leads to a dramatic increase in the drug dissolution rate. This process includes three steps: (1) a semi-continuous co-cr ystallization by a su-percritical anti-solvent process generating a solid dispersion, (2) a batch maturing step during which the powder mixture evolves towards a more intimate mixture, and (3) a final semicontinuous stripping step where residual solvent is extracted with some Eflu-cimibe and water.
The main novelty of this process lies in the cou-pling of these three steps, exhibiting a strong syner-gistic effect in the improvement of the dissolved drug
concentration of the drug. Comments on both processes
A new innovative and promising supercritical pro-cess but not yet fully understood and controlled; a more classical, usual one but better controlled and more advanced in terms of scaling up.
Concerning the supercritical process, the main limiting point is the use of organic solvent in the SAS step. It has to be pointed out that the co-crystalliza-tion step leads to an intimate mixing of the API and CD; this can be an advantage when the API is a volu-minous molecule that may present difficulties to be efficiently mixed. But this step is not needed in many others cases to improve the efficiency of the matur-ing step and therefore physical mixtures can be suf-ficient. This has been confirmed for instance for the binary Ketoprofen-β-CD10). In addition, the stripping
step is needed only when SAS step is performed; it is a typical extraction process where enhanced transfer properties of the supercritical CO2 are determining
parameters. Besides, to be industrially conceivable, SAS and stripping steps imply that supercritical CO2
is regenerated (a solvent/antisolvent separation is needed) to be recycled. The key-step that is the matur-ing step is a very simple one, easy to handle, and a “green” one, low energy-consuming (the main en-ergy requirement is when pressurizing the CO2). In
addition, it delivers a ready-to-use product without any further processing: it has been observed with the Ketoprofen-β-CD mixture that no additional water remained in the produced association complex, not needing then a subsequent stripping or drying step 10).
On a scaling-up point of view, in the SAS step, the ratio Solvent/Antisolvent has to be kept constant together with the API concentration in the solvent: these are the predominant invariant parameters and the scaling up could be performed as “scaling out” by setting lab-scale autoclaves with their nozzles in par-allel. As for the maturation step, the main invariant parameter that has to be kept constant when chang-ing scale is the mixture (API/CD/Water) composi-tion and duracomposi-tion, with mixing condicomposi-tions unchanged. Yet, in spite of its already proved efficiency, this step has to be further investigated in order to fully under-stand the phenomena implied. On a process point of view, the handling of the produced powders could also be improved. The longest step is the maturing one, which is 6 hours. In any case, this newly set-up process has proved to be highly effective concerning the in vivo bioavailability of the Eflucimibe, which was multiplied by 11 (AUC, Area Under the time
con-centration Curve ) in dog studies (unpublished data). As for the kneading process, the device used is more conventional and simple. Scaling-up is relatively easy to perform with the existing commercial devices using traditional approaches of chemical engineering like dimensional analysis and experimental design. This process performed with water avoids the use of organic solvent and works at low temperature level. The produced powder allows a significant enhance-ment of the API bioavailability. However, it has to be noticed that the operating parameters, in terms of formulation, have to be previously optimized in or-der to allow the scaling-up based on the capacities of commercial devices: a wrong formulation may induce a very high increase of the required torque, that is not acceptable on the mechanical point of view, by commercial devices.
Conclusion
Both processes resulted in a strong acceleration of the in vitro dissolution rate of the drug. Finally, in an
in vivo test, different Eflucimibe processed
formula-tions have been compared. In comparison with other technologies used (data not published) these two processes appeared to be the most effective, process (a) and (b) giving respectively a 8-fold and 11-fold in-crease in bioavailability.
Process (a) can be anticipated as a “green process”, as it does not use any organic solvent, but only a small amount of water, eliminated by final drying. It is fast, easily scalable and easy to monitor with Process Ana-lytical Technology (PAT) tools; it can be continuously monitored, evaluated and adjusted using validated in-process measurements, tests, controls, and in-process end-point. In addition, it needs fewer investments, the material is easy to clean, and it allows the treatment of large quantities.
Process (b) appears to be the most efficient. It uses SC-CO2 as antisolvent that can be recycled in
the process and only a small amount of DMSO as solvent eliminated during the final stripping step. A drawback may lie in the fact that it requires high-pressure equipment.
Depending on the physical-chemical properties (solubility...) of the active ingredient and on the con-text of drug development and production (NDA-New Drug Application, generics) depending on econom-ics, rationality and efficiency, and depending on how easy it is to obtain a good complexation percentage, energy needs, it can be better to use one or the other technique.
Acknowledgements
This article is dedicated by the authors to Profes-sor John A. Dodds, head of EMAC-CNRS UMR 2392, who proposed this idea of paper to KONA’s editorial committee. We wish him a happy new life after his retirement.
Pierre Fabre group is warmly acknowledged for providing the active molecule and for sponsoring this research.
A more detailed description of both processes have been published in two separate articles in the Euro-pean Journal of Pharmaceutical Sciences.
Abbreviations
ACAT Acyl-Coenzyme A O-acyltransferase
API Active Pharmaceutical Ingredient
AUC Area Under the time concentration Curve
BCS Biopharmaceutics Classification System
CD Cyclodextrin
β-CD Beta-Cyclodextrin γ-CD Gamma-Cyclodextrin
CO2 Carbon dioxyde
DMSO DiMethylSulfOxide
DSC Differential Scanning Calorimetry
ESEM Environmental Scanning Electron Micro-scope
FDA Food and Drug Administration
FTIR Fourier Transform InfraRed spectroscopy
GPC Gas Phase Chromatography
HPLC High Performance Liquid Chromatography
NDA New Drug Application
PAT Process Analytical Technology
Ppm Part per million
SAS Supercritical AntiSolvent
SDS Sodium Dodecyl Sulfate
SC-CO2 Supercritical Carbon Dioxide
UV UltraViolet spectroscopy
W/V Weight/Volume
W/w Weight/weight
Nomenclature
ΔP Net blade power consumption [W]
ρ Bulk density [kg.m-3]
N Blade rotational speed [rad.s-1]
R Blade radius [m]
D Blade diameter [m]
L Blade length [m]
H Height of powder bed [m]
g Gravitational constant [m.s-2]
Np Power number : Np =
Re Reynolds number : Re =
Fr Froude number : Fr =
I0/I FTIR absorbance ratio measured
respec-tively at 1572 cm-1 (I
0) and 1537 cm-1 (I)
References
１） Gil A.:Recherche de complexation entré une nouvelle entité chimique et des cyclodextrines par co-broyage et malaxage, Doctorat (PhD) de l’Université de Paris XI, sept. 2002.
２） Hutin S.:Recherche de conditions d’optimisation de la complexation d’actifs avec des cyclodextrines en milieu semi-solide, de la préformulation à l’étude de faisabilité industrielle, Doctorat (PhD) de l’Université de Paris XI, oct. 2005.
３） Fages J., Lochard H., Letourneau J.-J., Sauceau M., Rodier E. Particle Generation for Pharmaceutical Ap-plications Using Supercritical Fluid Technology. Pow-der Technol., 141, 2004, 219-226.
４） Amidon G. L., Lennernäs, H, Shah, V.P., Crison, J.R.: A theoretical basis for a Biopharmaceutics Drug Clas-sification: The correlation of in vitro drug product dissolution and in vitro bioavailability , Pharm.Res, 12, 1995, 413-420.
５） Baron, M, Chamayou, A, Marchioro, L., Raffi, J.: Radicalar probes to measure the action of energy on granular materials, Adv. Powder Technol, 16, 2005, 199-211.
６） Gines, J.M., Arias, M J., Perez-Martinez, J.I., Moyano, J.R., Morillo, E., Sanchez-Soto, PJ.:. Determination of the stoichiometry of 2,4-dichlorophenoxyacetic acid-b-cyclodextrin complexes in solution and solid state. Thermochim. Acta, 1998, 321, 53-58.
７） Faure A., Grimsey I.M., Rowe R.C., York P., Cliff M J.: Applicability of a scale-up methodology for wet granu-lation processes in Colette Gral High Shear Mixer-Granulators, Eur. J. Pharm. Sci, 1999, 8, 85-93.
８） Cliff, M J, Parker, M.D.: Scale-up of mixer granulator, in Proceedings of 12th Interphex Conference, Reed Ex-hibitions, Norwalk, CT, 1999, 17-32.
９） Van Hees T., Piel G., Evrard B., Otte X., Thunus L., Delattre L., Application of supercritical carbon dioxide for the preparation of a piroxicam beta-cyclodextrin in-clusion compound, Pharm. Res., 16, 1999, 1864-1870. 10） Bounaceur A., Rodier E., Fages J., Maturation of a
ketoprofen-b-Cyclodextrin mixture with supercritical carbon dioxide, J. Supercrit. Fluids, 41, 2007, 429-439. 11） Foster N.R., Mammucari R., Dehghani F.
Coprecipita-tion of pharmaceuticals using gas antisolvent tech-nique, Proceedings of the 8th Meeting on supercritical fluids, Bordeaux, France, 2002. Vol I, pp. 321-326. 12） Lochard H., Augmentation de la biodisponibilité d’un
principe actif pharmaceutique par voie supercritique, Doctorat (PhD) de l’Ecole des Mines de Paris, nov. 2003.
13） Rodier E., Lochard H., Sauceau M., Letourneau J J., Freiss B., Fages J., A three step supercritical process to improve the dissolution rate of Eflucimibe., Eur. J. Pharm. Sci., 26, 2005, 184-193.
14） Lochard H., Rodier E., Sauceau M., Letourneau J-J., Fages J. Particle generation by SAS process : effect of the operating conditions on the specific surface area of the powder, Proceedings of the 8th Meeting on supercritical fluids, Bordeaux, France, 2002. Vol I, pp. 109-114.
15） Barillaro V., Piel G., Bertholet S., Henry de Hasson-ville S., Evrard B., Delattre L., Inclusion of miconazole into cyclodextrins by means of supercritical carbon dioxide: influence of the addition of an acidic ternary compound., Proceedings of the 6th Int. Symp. Superc. Fluids, Versailles, 2003, 1897-1902.
16） Marongiu B., Piras A., Porcedda S., Lai A., Lai S., Prepa-ration and characterization of Imazadil/β-cyclodextrin inclusion complex by supercritical carbon dioxide and 13C Cp-Mas and 1H NMR Spectroscopy: Preliminary results., Proceedings of the 6th Int. Symp. Superc. Flu-ids, Versailles, 2003, 1903-1910.
Author’s short biography
Professor Jacques Fages
Professor Jacques Fages is currently director of the RAPSODEE research centre at
the Ecole des Mines d’Albi, ALBI, France. Under his leadership, RAPSODEE won
the French innovation award in 2006.
Professor Jacques FAGES graduated from the Institut National des Sciences Appli-quées (INSA Toulouse, France) in Biochemical engineering in 1979.
After a two-year experience as a mathematics teacher in Africa, he spent 15 years in several industrial companies as junior and then senior researcher between 1982 and 1996.
He obtained his HDR (Habilitation à Diriger des Recherches) in 1993 from Tou-louse University. He joined the Ecole des Mines d’Albi as a professor in 1996 where he was head of the Bio-industry final-year of engineering studies until 2005 when he was appointed director of RAPSODEE.
His present field of interest is the particle generation from supercritical fluids. He created a new research team in this domain in 1999 in Albi. In 1993 and 2003, he won two research awards given by ADERMIP an association for the development of research.
Professor Jacques FAGES is the author of more than 50 papers in international journals and book chapters and is the inventor of more than 15 international pat-ents. He has given many keynote lectures and has been member of several scien-tific committees of international conferences. He is member of the high pressure working party of the European Federation of Chemical Engineering. Since June 2007, he is the president of ISASF: International Society for the Advancement of Supercritical Fluids.
He was awarded in 2007 “Chevalier” in the national “Ordre des Palmes Aca-démiques” .
Elisabeth Rodier
Lecturer since 1996 at the Ecole des Mines d’Albi , Laboratoire RAPSODEE, Albi
(France).
Holder of a PhD (Chemical Engineering), performed in the 《Laboratoire des
Sci-ences du Génie Chimique》, CNRS, Nancy (France) since 1993 and of an Habilita-tion à Diriger des Recherches, Ecole des Mines d’Albi, Université Paul Sabathier, Toulouse (France), since 2006.
Current Research Interets: Production of divided solids using technologies based on the use of supercritical fluids, Characterisation of particles and porous media (zeta potential, sorption isotherms…).
Alain Chamayou
Born in 1962, Alain Chamayou is a Chemical Engineer from the “Ecole Nationale Supérieure de Génie Chimique” (Toulouse France), received his PhD in Process Engineering at the “Intsitut Nationa Polytechnique” of Toulouse in1993. Actually he is an Assistant Professor in the RAPSODEE research centre of the Ecole des Mines d’Albi where he develops research in the fields of fine grinding,, mechanosynthesis and dry-coating.
Historically, he began working on fine grinding with air-jet mills (PhD thesis of L. Godet 2001) with a population balance modelling approach. Then a part of his works were oriented to organic mecanosynthesis (PhD thesis of A. Gil-2002) us-ing this approach in order to improve the bioavailability of drug substances. More generally, mechanical actions are a way to combine (physically and/or chemically) particles in order to obtain new particles with desired user properties. He also extended the basic thematic of grinding (comminution) to co-grinding and then dry-coating (PhD Thesis of A.Vilela 2005) in order to design particles with specific properties. In parallel has developed collaborations with the university of Santiago of Chile to study the influence of ultrasound on grinding and co-grinding, and on products properties.
Michel Baron
Professor Michel Baron is currently Professor and Head of Pharmaceutical
Engi-neering Department at the Ecole des Mines d’Albi, Groupe des Ecoles des Mines,
Albi, France.
Dr. Baron received his pharmacist degree from the Paris XI University, his DEA (Organic Chem.) from the Paris VI University, and his PhD (Pharmaceutical Sci-ences) from the Paris V University, France.
He has served for 7 years as assistant professor at the University René Descartes in Paris, France.
He worked in industrial companies in France and Monaco for 7 years, in research and development of pharmaceutical active ingredients..
He then joined the Ecole des Mines d’Albi, France in 1993 where he developped
original studies for engineers and pharmacist-engineers double-diploma .
He has served as visiting professor at Tohoku University, Institute for Advanced Materials Processing, Japan, and Keio University, Faculty of Science and Technol-ogy, Japan.
His research interest in the Rapsodee Center-CNRS UMR 2392 are directed to-wards pharmaceutical process engineering and organic mechanochemistry.
